CML is a clonal stem cell disorder, characterized by increased proliferative capacity in the myeloid lineage, that is almost universally associated with a typical chromosomal translocation known as the Philadelphia chromosome. This is an acquired disorder, and although no specific etiologic agent has been identified, radiation exposure does lead to a significant increase in risk. There is an increasing incidence with advancing age, but the average age remains in the fifth and sixth decades of life.
The characteristic Philadelphia chromosome is a result of translocation of genetic material from chromosome 9 to chromosome 22. The gene on chromosome 9 has been identified as the Abelson proto-oncogene (abl). The region on chromosome 22 has been defined as the breakpoint cluster region (bcr). The rearrangement creates a bcr/abl fusion gene, which is believed to be pathophysiologically involved in the development of leukemia. Depending on the sensitivity of the detection method for the presence of the bcr/abl rearrangement, upward of 95% of all cases of CML demonstrate this very typical 9 : 22 translocation.
The clinical characteristics of CML involve a standard triphasic course of the disease, with an initial chronic phase followed by an accelerated phase and culminating in a blast phase, with the entire course of the disease spanning an average of approximately 3 years. The typical findings at the time of diagnosis include an elevated white blood cell (WBC) count, which may be mild or can exceed 200,000 cells/mL. Anemia or thrombocytopenia may contribute to the presenting symptoms. The most frequent complaints include fatigue, anorexia, abdominal discomfort, and early satiety related to splenomegaly and are generally gradual in onset. Splenomegaly is the most common physical finding, with more than 90% of the cases demonstrating an enlarged spleen. The accelerated phase of CML is heralded by progressive leukocytosis, despite therapy with worsening cytopenia and progressive splenomegaly. Blast crisis has the same clinical presentation as acute leukemia.
The diagnosis of CML is confirmed by the presence of a marked increased in granulocytes with the presence of immature myeloid cells in the peripheral blood. There is usually not a significant peripheral blast count. Eosinophils and basophils in the peripheral blood are common. Leukocyte alkaline phosphatase is typically low or zero in CML. The bone marrow shows hypercellularity with predominantly granulocytic differentiation. The presence of splenomegaly is further evidence for the diagnosis of CML. Chromosomal evidence of the Philadelphia chromosome is confirmatory; however, a rare case of Philadelphia chromosome-negative CML exists.
The treatment of CML is beginning to reap the benefit of decades of research into the pathophysiology of the disease. Until recently, there were no curative therapeutic strategies, and the therapeutic goal was to maintain controlled myelopoiesis in the chronic phase and accelerated phase; however, no therapy was known to delay the conversion to the accelerated phase (or blastic phase) of CML. Standard therapy has consisted of hydroxyurea delivered at 1 to 3 g per day by mouth, with a goal of maintaining the WBC count between 10,000 and 20,000. Direct inhibitors of the bcr/abl fusion protein are now able to impact on the disease with minimal toxicity.
Interferon-alpha has been shown to improve the survival of patients with CML compared with treatment with hydroxyurea. Interferon-alpha is generally initiated at 3 to 5 million units subcutaneously per day, and the response is maintained with a 3- to 5-day per week treatment schedule. Flu-like symptoms are common but frequently can be managed with acetaminophen.
Interferon-alpha improved the rate of karyotypic response, as well as the time of progression from chronic phase to accelerated or blastic phase, and was associated with a significant improvement in overall survival (72 months versus 52 months for hydroxyurea). Addition of chemotherapy can improve the percentage of patients achieving a cytogenetic remission. Unfortunately, few older patients have been included in the reported trials.
Bone marrow transplant has been an attractive option for younger patients; in fact, preliminary results suggest early transplant in the chronic phase is associated with the best outcome for those patients who have a human leukocyte antigen- (HLA-) compatible sibling. Unfortunately, two-thirds of the patients diagnosed with CML are either considered too old to undergo this intensive therapy or do not have HLA-compatible siblings.
The development of compounds to directly inhibit the bcr/abl fusion product has been a promising area of research. The fusion protein is a unique tyrosine kinase, and the first FDA-approved inhibitor of this kinase has recently been approved for patients with CML who cannot tolerate or have not responded to interferon. Initial results of the oral drug suggest excellent activity with minimal toxicity, which may be particularly important to elderly patients who tend to tolerate high doses of interferon poorly. A randomized trial comparing the oral kinase inhibitor (Gleevec) to interferon plus chemotherapy for newly diagnosed patients with CML is ongoing. It is possible that the payoff for years of research will be realized soon.
- Acute Leukemias
- Myeloproliferative Disorders
Revision date: July 5, 2011
Last revised: by Jorge P. Ribeiro, MD